The anterior segment of the eye comprises structures essential for vision and overall ocular health. Anterior segment dysgenesis (ASD) refers to a broad spectrum of eye diseases that occur when these structures do not form appropriately during fetal development. Children born with ASD can exhibit iris hypoplasia, misplaced pupils, hazy corneas, and corneal-iris adhesions. In addition, because the tissues responsible for intraocular pressure (IOP) regulation reside in the anterior segment, ASD is commonly associated with a severe form of childhood glaucoma - a progressive blinding disease for which increased IOP is the leading risk factor. Though early malformation of the anterior segment is known to result in a variety of eye disorders, the specific mechanisms underlying its proper development remain largely unidentified. Recent data has implicated both Notch and Bone Morphogenic Protein (BMP) signaling in the formation of the ciliary body, the site of aqueous fluid production. Specifically, in mice deficient for the Notch2 receptor, BMP signaling was significantly diminished and the ciliary body failed to develop. Furthermore, preliminary evidence suggests that these pathways may also be involved in development of the iridocorneal angle, a region involved in fluid drainage comprised of the trabecular meshwork and Schlemm's canal. The experiments proposed below will test the overarching hypothesis that Notch signaling acts upstream of BMP signaling in the development of anterior segment structures important for IOP regulation. Using mouse gain and loss of function alleles, I will examine the morphogenesis of the ciliary body and iridocorneal angle following perturbation of key proteins within the pathways of interest. In addition, I will assess the long-term effects of ASD on ocular physiology in adult mice. This work will define the temporal and spatial requirements of the Notch and BMP signaling pathways during the formation and later maintenance of important anterior eye structures. Results from these studies will ultimately provide fundamental insight into the developmental biology regulating anterior segment development, as well as identify molecular targets that may prove valuable in treating children with ASD.